PROJECT SUMMARY Nonmelanoma skin cancer (NMSC) is the most common malignancy in the United States representing a considerable public health burden. Pharmacological suppression of skin photocarcinogenesis has shown promise in preclinical and clinical studies, but more efficacious photochemopreventive agents are needed. Here, we test feasibility of harnessing pharmacological disruption of intracellular zinc homeostasis for photochemoprevention in vitro and in vivo. Employing the zinc ionophore and FDA-approved microbicidal agent zinc pyrithione (ZnPT), used worldwide in over-the-counter (OTC) topical consumer products, we will first (aim #1) explore tissue factors determining zinc-senistivity that may explain the exquisite vulnerability of malignant keratinocytes towards zinc ion overload. To this end, molecular determinants underlying altered zinc ion homeostasis in SCC will be examined (ZIP2 (SLC39A2) and ZnT6 (SLC30A6)). In aim #2, we will compare 'preventive' and 'interventional' efficacy of topical ZnPT in the SKH-1 murine photocarcinogenesis model substantiating feasibility of repurposing a safe, readily available topical OTC drug for zinc-directed photochemoprevention of solar UV-induced NMSC.